title: Effects of breast cancer resistance protein inhibitors and pharmaceutical excipients on decreasing gastrointestinal toxicity of camptothecin analogs.
abstract: OBJECTIVE
  To investigate the effect of breast cancer resistance protein (BCRP) inhibitors and pharmaceutical excipients on reducing the biliary excretion of camptothecins (CPT), ameliorating delayed-type diarrhea and intestinal mucosa damage induced by CPT.
  
  
  METHODS
  The cumulative biliary excretion of irinotecan (CPT-11) and hydroxycamptothecin (HCPT) with or without BCRP inhibitors and excipients was investigated in rats. The gastrointestinal toxicity, assessed as the diarrheal score, body weight change and microscopic pathological damage was also determined in rats.
  
  
  RESULTS
  Breast cancer resistance protein (BCRP) exhibited important effects on the biliary excretion of CPT. Coadministration of BCRP inhibitors such as GF120918 and cyclosporin A reduced the biliary excretion of CPT-11 and HCPT. Pharmaceutical excipients such as Pluronic F68 and PEG 2000 stearate also showed inhibitory effects on BCRP and similarly reduced CPT biliary excretion. The observed gastrointestinal toxicity was ameliorated by coadministration of BCRP inhibitors and excipients compared with injection of CPT-11 and HCPT alone.
  
  
  CONCLUSIONS
  The use of excipients as inhibitors of BCRP is safe and relatively non-toxic, and may lead to important pharmacotherapeutic benefits by decreasing the gastrointestinal toxicity of CPT.
authors.affiliation: Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xin-xin
authors.initials: XX
authors.lastname: Zhang
authors.forename: Wei-san
authors.initials: WS
authors.lastname: Pan
authors.forename: Li
authors.initials: L
authors.lastname: Gan
authors.forename: Chun-liu
authors.initials: CL
authors.lastname: Zhu
authors.forename: Yong
authors.initials: Y
authors.lastname: Gan
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001711:Biotransformation; D001943:Breast Neoplasms / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control; D005079:Excipients; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005079:Excipients; D009363:Neoplasm Proteins; D002166:Camptothecin